Abstract
Ketamine elicits rapid and durable antidepressant actions in treatment-resistant patients with mood disorders such as major depressive disorder and bipolar depression. The mechanisms might involve the induction of metaplasticity in brain regions associated with reward-related behaviors, mood, and hedonic drive, particularly the ventral tegmental area (VTA) and the nucleus accumbens (NAc). We have examined if ketamine alters the insertion of the GluA2 subunit of AMPA receptors (AMPAR), which determines calcium permeability of the channel, at glutamatergic synapses onto dopamine (DA) neurons in the VTA and spiny projection neurons (SPNs) in the Core region of the NAc. Mice received one injection of either saline or a low dose of ketamine 24 h before electrophysiological recordings were performed. We found that GluA2-lacking calcium-permeable (CP) AMPARs were present in DA neurons in the VTA of mice treated with saline, and that ketamine-induced the removal of a fraction of these receptors. In NAc SPNs, ketamine induced the opposite change, i.e., GluA2-lacking CP-AMPARs were inserted at glutamatergic synapses. Ketamine-induced metaplasticity was independent of group I metabotropic glutamate receptors (mGluRs) because an agonist of these receptors had similar effects on glutamatergic transmission in mice treated with saline and in mice treated with ketamine in both VTA DA neurons and in the NAc. Thus, ketamine reduces the insertion of CP-AMPARs in VTA DA neurons and induces their insertion in the NAc. The mechanism by which ketamine elicits antidepressant actions might thus involve an alteration in the contribution of GluA2 to AMPARs thereby modulating synaptic plasticity in the mesolimbic circuit.
Highlights
Ketamine elicits rapid and lasting antidepressant actions when administered in low doses to treatment-resistant patients with mood disorders such as major depressive disorder and bipolar depression [1, 2]
Ketamine induces the removal of a fraction of GluA2-lacking CP-AMPA receptors (AMPAR) at glutamatergic synapses in ventral tegmental area (VTA) DA neurons To investigate possible changes induced by ketamine in the involvement of GluA2 in synaptic AMPARs in VTA DA neurons, we first performed current/voltage (I/V) relationship analyses of
We examined the effect of NASPM trihydrochloride, a selective antagonist of GluA2-lacking CP-AMPARs, on the amplitude of AMPAR-Excitatory postsynaptic currents (EPSCs)
Summary
Ketamine elicits rapid and lasting antidepressant actions when administered in low doses to treatment-resistant patients with mood disorders such as major depressive disorder and bipolar depression [1, 2]. Ketamine was suggested to modify or induce long-term alterations in the strength of glutamatergic synaptic transmission, e.g., long-term potentiation (LTP) and longterm depression (LTD). We previously demonstrated that ketamine prevented LTP induction in the Core area of the nucleus accumbens (NAc) [3] This effect was observed one day following the injection and persisted for one week, demonstrating the ability of ketamine to induce lasting metaplasticity in the mesolimbic circuit. In dopamine neurons in the ventral tegmental area (VTA DA) from mice that received one injection of ketamine, responses mediated by AMPA receptors (AMPARs) were depressed. Loss of LTP in the NAc by a single injection of ketamine was associated with altered phosphorylation of the AMPAR GluA1 subunit Contrasting with this observation in the NAc, LTD induced by ketamine in VTA DA neurons was not associated with a modified phosphorylation of GluA1. The precise mechanisms by which ketamine blunts increase in glutamatergic synaptic transmission in the NAc and promotes a novel form of LTD in VTA DA neurons remain to be resolved
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